Project Summary The long-term objective of this proposal is to identify the role of non-coding RNAs and their target genes that could potentially contribute to the development and progression of diabetic nephropathy (DN). We propose to convincingly establish the role of long non-coding RNA (lncRNA) Tug1 (Taurine up-regulated gene 1) and its downstream targets as key mediators and potential therapeutic targets in DN. Our hypothesis is based on several novel observations: 1) we have found that Tug1 overexpression in vivo can attenuate progression of diabetic nephropathy, 2) we have identified for the first time a direct physical interaction between a long noncoding RNA and PGC-1? (the peroxisome proliferator-activated receptor ? coactivator 1a or Ppargc1a), a master regulator of mitochondria transcriptional program, 3) mechanistically, we show that Tug1 binds to an upstream enhancer element of the PGC-1? gene to regulate PGC-1? transcription, and 4) the interaction between Tug1 and PGC-1? modulates mitochondrial bioenergetics. These results provide compelling initial evidence that Tug1 represents a therapeutic target that might be useful in improving mitochondrial function in DN. In aim 1, we will test whether Tug1-mediated renoprotection in DN is accomplished through a PGC-1?-dependent improvement in mitochondrial bioenergetics in vivo. By adapting a genetic approach, we will address two central questions in this aim: 1) does targeting PGC-1? in podocytes modulate the course of DN progression? and 2) is the effect of Tug1-mediated renoprotection primarily accomplished via its direct regulatory role on PGC-1?? In aim 2, we will examine whether Tug1 exerts PGC- 1?-independent effects in podocytes. It is well recognized that non-coding RNAs have numerous targets, and we recognize that other targets of Tug1 may also contribute to the modulatory effects of Tug1. In this regards, we have unexpectedly uncovered a novel role for Tug1 as a potential regulator of Wilm's Tumor 1 (WT1), a master podocyte transcription factor. We hypothesize that Tug1 exerts a regulatory role on podocytes homeostasis via its modulatory role on WT1 and its related targets. Finally, in Aim 3, we will examine the mechanisms by which Tug1 is regulated in the diabetic milieu. The findings of this application will provide a significant advance in three aspects: first, this proposal represents a new therapeutic approach to the treatment of patients with DN. Second, our research will shed further light on the pathobiology of PGC-1? in DN. And finally, we will employ a genetic approach to validate a direct link between Tug1 and its downstream targets involved in the pathogenesis of DN.